Better than BOLD. Three recent proof-of-concept studies suggest that functional ultrasound (fUS) imaging, a method capable to be used simultaneously as PharmacoMRI, fMRI and rs-fMRI, provides a powerful readout to study the effects of pharmacological agents on the brain, without the bias of anesthesia. Pharmacological-fUS or pharmaco-fUS is now validated in rats and mouse models as an interesting tool to complement behavorial studies, with solid results obtained in small cohorts of animals.
In the first study, a collaborative work of Iconeus founders, Rabut and al. have shown that scopolamine, a major preclinical drug to model Alzheimer’s disease, leads to time- and dose depend changes of cerebral functional connectivity in awake mice. A machine-learning approach was used to extract a robust pharmacological score or fingerprint of the drug effects on the brain from a relatively small cohort of mice. The pharmacological pertinence of the scopolamine score was demonstrated by reversal through the antagonist milameline and the peripherally-restricted methyl-scopolamine.
The second and third studies, both from the pharmaceutical company Theranexus, demonstrated how fUS can be useful for drug development. In the first study the authors compared the hemodynamic response of the brain to the administration of donepezil alone (potent acetylcholinesterase inhibitor, largely used worldwide to alleviate cognitive symptoms in Alzheimer's disease) versus donepezil combined with mefloquine (a new drug targeting connexins, the proteins involved in astrocyte network organization). They have showed that although administration of donepezil or mefloquine alone at low dose had only very limited effects on the signal compared to the baseline, their combination produced marked hemodynamic effects in the hippocampus, in line with previously published behavioral data demonstrating a synergic interaction between both drugs. These results confirmed the potential of the combined treatment and provided new insights on how both drugs could interact. In the third study, Theranexus investigated the effect of atomoxetine, a potent norepinephrine reuptake inhibitor and non-stimulant treatment of attention-deficit/hyperactivity-disorder, in anesthetized rats at increasing doses (0.3, 1 and 3 mg/kg). Dose-dependent temporal variations of the cerebral blood flow were observed, particularly in brain regions involved in vision.
These three studies demonstrate that pharmaco-fUS could improve our understanding of the mechanism of action of drugs in the brain and might accelerate the development of new drugs targeting neurological disorders. Pharmaco-fUS does not require the animals to be anesthetized, and therefore yields a quantitative assessment of brain functions without anesthesia-induced bias. Pharmaco-fUS currently acquires cross-sectional (2D) images of the rodent brain. Current development of volumetric (3D) imaging is expected to enable the assessment of drug effects in the entire rodent brain within a single imaging session.
Links to full-text publications:
- Rabut C, Ferrier J, Bertolo A, Osmanski B, Mousset X, Pezet S, et al. Pharmaco-fUS: Quantification of pharmacologically-induced dynamic changes in brain perfusion and connectivity by functional ultrasound imaging in awake mice. NeuroImage 2020 doi:10.1016/j.neuroimage.2020.117231
- Vidal B, Droguerre M, Valdebenito M, Zimmer L, Hamon M, Mouthon F, Charvériat M. Pharmaco-fUS for Characterizing Drugs for Alzheimer’s Disease – The Case of THN201, a Drug Combination of Donepezil Plus Mefloquine. Frontiers in Neuroscience 2020 doi:10.3389/fnins.2020.00835
- Vidal B, Droguerre M, Venet L, Zimmer L, Valdebenito M, Mouthon F, Charvériat M. Functional ultrasound imaging to study brain dynamics: Application of pharmaco-fUS to atomoxetine. Neuropharmacology 2020 doi:10.1016/j.neuropharm.2020.108273